The long-term goal of the proposed study is to provide the scientific basis for public health strategies to reduce incidence of and mortality from colorectal cancer. Several lines of evidence suggest that a high fat diet increases the risk of colorectal cancer. While ecologic studies and earlier case-control studies demonstrated a strong association with high fat intake, the results from cohort studies and recent case-control studies have rather been inconsistent. These discrepancies may indicate some genetic susceptibility that modify the effects of a high fat diet. One of the major mechanistic bases for the roles of fat in colorectal carcinogenesis is intracolonic exposure to potentially carcinogenic substances which are generated from lipid and its metabolites with fecal bacterial activities. In this context fat absorption may play a key role in determining the effects of a high fat diet on colorectal cancer risk via modifying the levels of luminal exposure to potentially carcinogenic metabolites. Recently, two common genetic polymorphisms (FABP2 and Apo E) that affect intestinal fat absorption and bile acid secretion have been reported and associated with risks of cardiovascular diseases, diabetes and dementia. We hypothesize that individuals with genotypes for lower intestinal absorption, which results in more intracolonic exposure to potentially carcinogenic substances, have a higher risk of developing colorectal cancer in relation to a high fat diet. To test this hypothesis, we propose to conduct a population-based case-control study in Metropolitan Detroit taking an advantage of the SEER Cancer Registry. We plan to interview 2000 cases and 2000 controls for their usual diet to estimate fat and other nutrient intake and collect blood or buccal cell specimens for genotyping assays. Specific aims of the study are (1) To determine whether the genotype, FABP2 A54, Apo E2/E3 or a combination of these, is associated with risk of colorectal cancer; (2) To determine whether the effect of a high fat diet on colorectal cancer risk is more pronounced in the subjects with these genotypes; and (3) To determine if the above interactions are modified by intake of other dietary components, such as fiber, calcium and iron, which affect luminal lipid metabolism. The results from the proposed study would provide useful information for effective dietary modification in primary prevention for colorectal cancer. In addition, accumulated dietary data and biological specimens will serve as an important resource for future research on other nutrient-gene interactions.